Paroxysmal nocturnal hemoglobinuria (PNH; also called Marchiafava-Micheli syndrome) is a rare, generally acquired (Luzzatto, L. Blood 122 (7): 1099-1100), life-threatening disease of the blood characterized by complement-induced intravascular hemolytic anemia (anemia due to destruction of red blood cells in the bloodstream), red urine (due to the appearance of hemoglobin in the urine) and thrombosis.
PNH is the only hemolytic anemia which is most often caused by an acquired (rather than inherited) intrinsic defect in the cell membrane (deficiency of glycophosphatidylinositol leading to absence of protective proteins on the membrane; Kumar Vinay et al. Robbins Basic Pathology (8th ed.). Saunders Elsevier. p. 432). It may develop on its own (“primary PNH”) or in the context of other bone marrow disorders such as aplastic anemia (“secondary PNH”). Only a minority (26%) have the telltale red urine in the morning that originally gave the condition its name (Parker et al. Blood 106 (12): 3699-709). Allogeneic bone marrow transplantation is the only curative therapy, but has significant rates of both mortality and ongoing morbidity.
The monoclonal antibody eculizumab (Soliris) has been found to be effective at reducing the need for blood transfusions, improving quality of life, and reducing the risk of thrombosis (Brodsky, R A Blood 113 (26): 6522-7). Eculizumab specifically binds to the terminal Complement component 5, or C5, which acts at a late stage in the complement cascade. When activated, C5 is involved in activating host cells, thereby attracting pro-inflammatory immune cells, while also destroying cells by triggering pore formation. By inhibiting the complement cascade at this point, the normal, disease-preventing functions of proximal complement system are largely preserved, while the properties of C5 that promote inflammation and cell destruction are impeded (Brodsky et al. (2009) Hematology: Basic Principles and Practice (Philadelphia, Pa.: Churchill Livingstone): 385-395).
A need exists for additional therapies that target C5, for use either as a substitute or in combination with eculizumab.
Double-stranded RNA (dsRNA) agents possessing strand lengths of 25 to 35 nucleotides have been described as effective inhibitors of target gene expression in mammalian cells (Rossi et al., U.S. Pat. No. 8,084,599 and U.S. Patent Application No. 2005/0277610). dsRNA agents of such length are believed to be processed by the Dicer enzyme of the RNA interference (RNAi) pathway, leading such agents to be termed “Dicer substrate siRNA” (“DsiRNA”) agents. Additional modified structures of DsiRNA agents were previously described (Rossi et al., U.S. Patent Application No. 2007/0265220). Effective extended forms of Dicer substrates have also recently been described (Brown, U.S. Pat. No. 8,349,809 and U.S. Pat. No. 8,513,207).